Kegg Pathway: Alzheimer's disease

Neurosci Bull. 2009 Dec; 25(6): 391-396
Luo HB, Yang JS, Shi XQ, Fu XF, Yang QD

Objective Excessive aluminum (Al) exposure impairs neurocognitive function in humans and animals. Epidemiologic studies have shown a potential linkage between chronic Al exposure and Alzheimer's disease. The present study aims to evaluate the effects of tetrahydroxy stilbene glucoside (TSG), the extract from herbal medicine Polygoni Multiflori, on cognitive impairment and the over-expression of hippocampal amyloid precursor protein (APP) induced by chronic exposure to Al in rats. Methods Rats were treated with 0.3% aluminum chloride (AlCl3) prepared in the drinking water for 90 d. AlCl3-treated animals were then randomly assigned to receive vehicle, TSG (4 g/kg), or Vitamin E (VE; 40 mg/kg) treatment for 5 months. VE served as a positive control. The effect of TSG was evaluated by passive avoidance task, and APP expression was evaluated by Western blotting. Results Following exposure to AlCl3 for 90 d, animals displayed a striking decrease (> 80%) in step-through latency in the passive avoidance task and a significant increase in the expression of APP in the hippocampus. Both TSG and VE significantly ameliorated the performance impairment in the passive avoidance task, and suppressed the over-expression of APP. Moreover, the effects of TSG, but not of VE, were in a time-dependent manner. Conclusion TSG may possess therapeutic effects against Alzheimer's disease.

Am J Hypertens. 2009 Nov 19;
Nagai M, Hoshide S, Kario K

Although hypertension is well known as a cause of vascular dementia (VaD), recent findings highlight the role of hypertension in the pathogenesis of Alzheimer's disease (AD) as well as mild cognitive impairment (MCI). Recent studies have shown that disruption of diurnal blood pressure (BP) variation is closely associated with cognitive impairment via injury of the small cerebral arteries indicating that long-standing hypertension constitutes a risk of brain matter atrophy or white matter lesions (WMLs). In several clinical trials, BP-lowering with antihypertensive agents was suggested to reduce the risk of dementia or cognitive decline. This review paper focuses on the role of hypertension as a risk factor for cognitive impairment, and summarizes current knowledge on the relationships between ambulatory BP monitoring (ABPM) and cognitive impairment. Finally, an overview of the impact of antihypertensive therapy on dementia prevention is provided.American Journal of Hypertension 2009; doi:10.1038/ajh.2009.212.

Proc Natl Acad Sci U S A. 2009 Nov 19;
Ryan SD, Whitehead SN, Swayne LA, Moffat TC, Hou W, Ethier M, Bourgeois AJ, Rashidian J, Blanchard AP, Fraser PE, Park DS, Figeys D, Bennett SA

Perturbation of lipid second messenger networks is associated with the impairment of synaptic function in Alzheimer disease. Underlying molecular mechanisms are unclear. Here, we used an unbiased lipidomic approach to profile alkylacylglycerophosphocholine second messengers in diseased tissue. We found that specific isoforms defined by a palmitic acid (16:0) at the sn-1 position, namely 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF) and 1-O-hexadecyl-sn-glycero-3-phosphocholine (C16:0 lyso-PAF), were elevated in the temporal cortex of Alzheimer disease patients, transgenic mice expressing human familial disease-mutant amyloid precursor protein, and human neurons directly exposed to amyloid-beta(42) oligomers. Acute intraneuronal accumulation of C16:0 PAF but not C16:0 lyso-PAF initiated cyclin-dependent kinase 5-mediated hyperphosphorylation of tau on Alzheimer disease-specific epitopes. Chronic elevation caused a caspase 2 and 3/7-dependent cascade resulting in neuronal death. Pharmacological inhibition of C16:0 PAF signaling, or molecular strategies increasing hydrolysis of C16:0 PAF to C16:0 lyso-PAF, protected human neurons from amyloid-beta(42) toxicity. Together, these data provide mechanistic insight into how disruptions in lipid metabolism can determine neuronal response to accumulating oligomeric amyloid-beta(42).

J Biol Chem. 2009 Nov 19;
Yamakawa H, Yagishita S, Futai E, Ishiura S

The amyloid-beta (Abeta) peptide, widely known as the causative molecule of Alzheimer's disease (AD), is generated by the sequential cleavage of amyloid precursor protein (APP) by the aspartyl proteases BACE1/beta-secretase and presenilin/gamma-secretase. Inhibition of BACE1, therefore, is a promising strategy for preventing the progression of AD. However, beta-secretase inhibitors (BSIs) exhibit unexpectedly low potency in cells expressing ''Swedish mutant'' APP (APPswe) and in the transgenic mouse Tg2576, an AD model overexpressing APPswe. The Swedish mutation dramatically accelerates beta-cleavage of APP and hence the generation of Abeta; this acceleration has been assumed to underlie the poor inhibitory activity of BSI against APPswe processing. Here, we studied the mechanism by which the Swedish mutation causes this BSI potency decrease. Surprisingly, decreased BSI potency was not observed in an in vitro assay using purified BACE1 and substrates, indicating that the accelerated beta-cleavage resulting from the Swedish mutation is not its underlying cause. By focusing on differences between the cell-based and in vitro assays, we have demonstrated here that the potency decrease is caused by the aberrant subcellular localization of APPswe processing and not by accelerated beta-cleavage or the accumulation of the carboxyl-terminal fragment of beta-cleaved APP (betaCTF). Because most patients with sporadic AD express wild-type APP, our findings suggest that the wild-type mouse is superior to the Tg2576 mouse as a model for determining the effective dose of BSI for AD patients. This work provides novel insights into the potency decrease of BSI and valuable suggestions for its development as a disease-modifying agent.

Clin Chem. 2009 Nov 19;
Dean RA, Shaw LM

Eval Health Prof. 2009 Nov 18;
Solomon PR, Michalczuk DE

The growing use of complementary and alternative medications (CAM) for cognitive enhancement in both healthy elderly and patients with Alzheimer's disease (AD) and other dementing disorders has led to rapidly growing literature with conflicting results. There are studies that suggest benefit from CAM in both the healthy elderly and dementing patients as well as studies that suggest no benefit for either group. Because of the lack of regulatory oversight (e.g., Food and Drug Administration [FDA], European Medicines Agency [EMeA]), there are currently no generally accepted guidelines to standardize the types of studies that are conducted. Due to the absence of guidelines that set standards for study design, outcomes, and analysis, it is difficult to compare studies with conflicting results. For example, Ginkgo biloba has been shown both to provide benefit and no benefit on cognition in both healthy elderly and patients with AD. Reconciling these divergent studies has been challenging because both sides often use divergent methodologies and designs and widely varying cognitive measures that may or may not be validated in the populations being studied. In this article, the authors suggest a roadmap for establishing guidelines for the evaluation of CAM in cognition. They then apply these guidelines to the conflicting literature on Ginkgo to determine whether they might help resolve the conflicting results.

Neurobiol Aging. 2009 Nov 17;
Brickman AM, Siedlecki KL, Muraskin J, Manly JJ, Luchsinger JA, Yeung LK, Brown TR, Decarli C, Stern Y

OBJECTIVE: White matter hyperintensities (WMH), visualized on T2-weighted MRI, are thought to reflect small-vessel vascular disease. Much like other markers of brain disease, the association between WMH and cognition is imperfect. The concept of reserve may account for this imperfect relationship. The purpose of this study was to test the reserve hypothesis in the association between WMH severity and cognition. We hypothesized that individuals with higher amounts of reserve would be able to tolerate greater amounts of pathology than those with lower reserve. METHODS: Neurologically healthy older adults (n=717) from a community-based study received structural MRI, neuropsychological assessment, and evaluation of reserve. WMH volume was quantified algorithmically. We derived latent constructs representing four neuropsychological domains, a measure of cognitive reserve, and a measure of brain reserve. Measures of cognitive and brain reserve consisted of psychosocial (e.g., education) and anthropometric (e.g., craniometry) variables, respectively. RESULTS: Increased WMH volume was associated with poorer cognition and higher cognitive and brain reserve were associated with better cognition. Controlling for speed/executive function or for language function, those with higher estimates of cognitive reserve had significantly greater degrees of WMH volume, particularly among women. Controlling for cognitive functioning across all domains, individuals with higher estimates of brain reserve had significantly greater WMH volume. CONCLUSIONS: For any given level of cognitive function, those with higher reserve had more pathology in the form of WMH, suggesting that they are better able to cope with pathology than those with lower reserve. Both brain reserve and cognitive reserve appear to mitigate the impact of pathology on cognition.

Neurobiol Aging. 2009 Nov 17;
Schuur M, Ikram MA, van Swieten JC, Isaacs A, Vergeer-Drop JM, Hofman A, Oostra BA, Breteler MM, van Duijn CM

Cathepsin D (CTSD) is a gene involved in amyloid precursor protein processing and is considered a candidate for Alzheimer's disease (AD). The aim of the current study was to examine if variation in CTSD increases the risk of AD. We performed a candidate-gene analysis in a population-based cohort study (N=7983), and estimated the effect of CTSD on the risk of AD. Additionally, a large meta-analysis was performed incorporating our data and previously published data. The T-allele of CTSD rs17571 was associated with an increased risk of AD (p-value 0.007) in the Rotterdam Study. This association was predominantly found in APOE varepsilon4 noncarriers. A meta-analysis of previously published data showed a significantly increased risk of AD in carriers of the T-allele of rs17571 (OR 1.22, 95% CI 1.03-1.44), irrespective of APOE varepsilon4 carrier status. This study adds to the evidence that CTSD increases the risk of AD, although the effect size is moderate.

Can J Aging. 2009 Dec; 28(4): 323-336
Chiu T, Marziali E, Colantonio A, Carswell A, Gruneir M, Tang M, Eysenbach G

ABSTRACTThe aim of this study was to assess the usability of a new Internet-based Caregiver Support Service (ICSS) and evaluate its effects on health outcomes of Chinese Canadians who cared for a family member with dementia. Demographic and questionnaire data were collected from 28 participants, and in-depth interviews were conducted with 10 participants. Results showed that non-users reported higher levels of burden post-intervetion, and frequent users showed post-intervention reduction in experienced burden. Traditional beliefs shaped caregivers' needs; also, ethno-cultural-linguistic contexts affected system usability and were associated with usage behaviour. This study indicates that caregivers can benefit from receiving professional support via asynchronous e-mails and a dedicated information web site. The ICSS is a feasible approach for supporting caregivers who prefer an alternative service model. This emerging service requires more research in: enhanced technology design, service delivery models for immigrant caregivers, and evaluation of effectiveness and cost-effectiveness.

CNS Neurosci Ther. 2009 Nov 19;
Caraci F, Battaglia G, Bruno V, Bosco P, Carbonaro V, Giuffrida ML, Drago F, Sortino MA, Nicoletti F, Copani A

Alzheimer's disease (AD) is a neurodegenerative disorder that affects more than 37 million people worldwide. Current drugs for AD are only symptomatic, but do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized by the presence of ss-amyloid (Abeta) plaques, neurofibrillary tangles, and neuronal loss. The identification of the molecular determinants underlying AD pathogenesis is a fundamental step to design new disease-modifying drugs. Recently, a specific impairment of transforming-growth-factor-beta1 (TGF-beta1) signaling pathway has been demonstrated in AD brain. The deficiency of TGF-beta1 signaling has been shown to increase both Abeta accumulation and Abeta-induced neurodegeneration in AD models. The loss of function of TGF-ss1 pathway seems also to contribute to tau pathology and neurofibrillary tangle formation. Growing evidence suggests a neuroprotective role for TGF-beta1 against Abeta toxicity both in vitro and in vivo models of AD. Different drugs, such as lithium or group II mGlu receptor agonists are able to increase TGF-beta1 levels in the central nervous system (CNS), and might be considered as new neuroprotective tools against Abeta-induced neurodegeneration. In the present review, we examine the evidence for a neuroprotective role of TGF-beta1 in AD, and discuss the TGF-beta1 signaling pathway as a new pharmacological target for the treatment of AD.

Curr Pharm Des. 2009; 15(31): 3644-3655
Fernández-Gamba A, Leal MC, Morelli L, Castaño EM

Insulin-degrading enzyme (IDE) or insulysin is a highly conserved Zn(2+) -dependent endopeptidase with an "inverted" HxxEH motif. In vivo, IDE contributes to regulate the steady state levels of peripheral insulin and cerebral amyloid beta peptide (Abeta) of Alzheimer's disease. In vitro, substrates of IDE include a broad spectrum of peptides with relevant physiological functions such as atrial natriuretic factor, insulin-like growth factor-II, transforming growth factor-alpha, beta-endorphin, amylin or glucagon. The recently solved crystal structures of an inactive IDE mutant bound to four different substrates indicate, in accordance with previous compelling biochemical data, that peptide backbone conformation and size are major determinants of IDE recognition and substrate selectivity. IDE-N and IDE-C halves contribute to substrate binding and may rotate away from each other leading to open and closed conformers that permit or preclude the entry of substrates. Noteworthy, stabilization of substrate beta strands in their IDE-bound form may explain the preference of IDE for peptides with a high tendency to self-assembly as amyloid fibrils. These structural requirements may underlie the capability of some amyloid peptides of forming extremely stable complexes with IDE and raise the possibility of a dead-end chaperone-like function of IDE independent of catalysis. Furthermore, the recent recognition of IDE as a varicella zoster virus receptor and its putative involvement in muscle cell differentiation, steroid receptor signaling or proteasome modulation suggest that IDE is a multi-functional protein with broad and relevant roles in several basic cellular processes. Accordingly, IDE functions, regulation or trafficking may partake in the molecular pathogenesis of major human diseases and become potential targets for therapeutic intervention.

Neurol Sci. 2009 Nov 19;
Lin K, Tang M, Han H, Guo Y, Lin Y, Ma C

It has recently been shown that GAB2 alleles modify the risk for late-onset Alzheimer disease (LOAD) in apolipoprotein E (ApoE)epsilon4 allele carriers in a genome-wide association study. Some studies subsequently in Caucasians population, though not all, have demonstrated that GAB2 polymorphisms might be associated with LOAD susceptibility. The aim of this study is to evaluate the reported polymorphisms (rs2373115 and rs1385600) and GAB2 haplotypes (rs2373115-rs1385600) for an interaction with the ApoEepsilon4 allele in a cohort of Chinese LOAD. We conducted a case-control study in 292 LOAD and 227 non-demented controls from the Chinese Han population. Our study does not find any association between the two tested SNPs and GAB2 haplotypes and LOAD or any synergetic interaction between the SNPs and ApoE either. However, since the sample size required to show this point is large, our finding needs to be confirmed by a large independent sample of Chinese population.

J Mol Model. 2009 Nov 20;
Haeffner F, Barnham KJ, Bush AI, Brinck T

A mechanism for the oxidation of a dimeric beta-amyloid copper ion complex is proposed based on DFT calculations. It involves the Met35 residue, which is believed to be important in the neurotoxicity causing Alzheimer's disease. Oxidation of Met35 is found to proceed readily with dioxygen when two Met35 residues are close to each other and the copper ion. This indicates that oxidants, such as hydrogen peroxide, are not necessary for oxidation of beta-amyloid copper ion complexes. Understanding these processes could be pivotal in gaining more knowledge of this complex disease and for the development of therapeutic treatments.

Ann Nucl Med. 2009 Nov 19;
Asai M, Fujikawa A, Noda A, Miyoshi S, Matsuoka N, Nishimura S

OBJECTIVE: [(18)F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) is a useful tool for measuring the regional cerebral metabolic rate of glucose (rCMRglu), which is an index of neuronal activity. Donepezil, an acetylcholine esterase inhibitor (AChEI), has been recommended as a treatment option for patients with Alzheimer's disease (AD). We aimed to characterize the effects of donepezil on rCMRglu using FDG-PET in non-human primates. METHODS: We investigated the effects of administration of donepezil (500 mug/kg, i.m.), the non-selective muscarinic ACh receptor antagonist scopolamine (30 mug/kg, i.m.), and the coadministration of both drugs on the rCMRglu of conscious young rhesus monkeys. RESULTS: Donepezil increased the rCMRglu in all regions of interest except in the thalamus. Scopolamine treatment also increased the rCMRglu in all regions of interest except the cerebellum and thalamus. However, these effects disappeared with coadministration of the drugs. CONCLUSIONS: This PET study showed that administration of donepezil or scopolamine alone increased the rCMRglu in conscious rhesus monkeys. We also found that the donepezil-induced increase was abolished by simultaneous administration of scopolamine, suggesting that muscarinic ACh receptor function plays an important role in the effect of donepezil.

J Nutr Health Aging. 2009; 13(10): 899-905
Nelson C, Wengreen HJ, Munger RG, Corcoran CD

Objective: To examine associations between dietary and supplemental folate, vitamin B-12 and vitamin B-6 and incident Alzheimer's disease (AD) among elderly men and women. Design, Setting and Participants: Data collected were from participants of the Cache County Memory, Health and Aging Study, a longitudinal study of 5092 men and women 65 years and older who were residents of Cache County, Utah in 1995. Measurements: Multistage clinical assessment procedures were used to identify incident cases of AD. Dietary data were collected using a 142-item food frequency questionnaire. Cox Proportional Hazards (CPH) modeling was used to determine hazard ratios across quintiles of micronutrient intake. Results: 202 participants were diagnosed with incident AD during follow-up (1995-2004). In multivariable CPH models that controlled for the effects of gender, age, education, and other covariates there were no observed differences in risk of AD or dementia by increasing quintiles of total intake of folate, vitamin B-12, or vitamin B-6. Similarly, there were no observed differences in risk of AD by regular use of either folate or B6 supplements. Conclusion: Dietary intake of B-vitamins from food and supplemental sources appears unrelated to incidence of dementia and AD. Further studies examining associations between dietary intakes of B-vitamins, biomarkers of B-vitamin status and cognitive endpoints are warranted.

J Nutr Health Aging. 2009; 13(10): 890-892
Voisin T, Sourdet S, Cantet C, Andrieu S, Vellas B

Objectives: There is lack of data on the frequency and the causes of hospitalization in mild to moderate Alzheimer's disease (AD) patients. The aims of the present study were to evaluate the frequency and the causes of hospitalization in a large prospective cohort of mild to moderate patients with AD. Design: Six hundred and eighty-six AD patients from the French Network on AD (REAL.FR) were followed up and assessed every 6 months for 2 years. During follow-up, all events occurring between two visits, in particular hospital admissions or nursing home placements were carefully recorded. Results: Annual incidences for hospitalizations were 26.2% (95% CI, 22.5 to 29.7). After two years, 202 subjects were hospitalized for 296 hospitalizations. 139 subjects were hospitalized once, 40 twice, 13 three times, 4 four times and 2 five times during the two-year follow-up. The duration of hospitalization was 14.3 +/- 23.5 days. For repeated hospitalizations, the time interval between the first and the second hospitalization was 176.4 days (SD 150.2) and the cause of multiple hospitalizations was most different. Fractures and falls not causing fracture were the main reasons for hospital admission (20.9%), followed by cardiovascular disorders (14.5%) and by behavioural disorders (11.0%). Admission due to associated diseases or life events was the main reason for hospitalization (75.7%). Conclusions: Hospitalization is a frequent event for AD patients even at mild to moderate stage of the disease. In this cohort, the major causes for hospital admission were due to associated diseases or life events and not due to the direct consequences of the disease itself.

PLoS One. 2009; 4(11): e7900
Giliberto L, Matsuda S, Vidal R, D'Adamio L

BACKGROUND: Mutations in the integral membrane protein 2B [1], also known as BRI(2)[2], a type II trans-membrane domain protein cause two autosomal dominant neurodegenerative diseases, Familial British and Danish Dementia [3]. In these conditions, accumulation of a C-terminal peptide (ABri and ADan) cleaved off from the mutated precursor protein by the pro-protein convertase furin [4], leads to amyloid deposition in the walls of blood vessels and parenchyma of the brain. Recent advances in the understanding of the generation of amyloid in Alzheimer's disease has lead to the finding that BRI(2) interacts with the Amyloid Precursor Protein (APP), decreasing the efficiency of APP processing to generate Abeta [5], [6], [7]. The interaction between the two precursors, APP and BRI(2), and possibly between Abeta and ABri or ADan, could be important in influencing the rate of amyloid production or the tendency of these peptides to aggregate. METHODOLOGY/PRINCIPAL FINDINGS: We have generated the first BRI(2) Danish Knock-In (FDD(KI)) murine model of FDD, expressing the pathogenic decamer duplication in exon 6 of the BRI(2) gene. FDD(KI) mice do not show any evident abnormal phenotype, with normal brain histology and no detectable amyloid deposition in blood vessel walls or parenchyma. CONCLUSIONS/SIGNIFICANCE: This new murine mouse model will be important to further understand the interaction between APP and BRI(2), and to provide insights into the molecular basis of FDD.

PLoS Biol. 2009 Nov; 7(11): e1000245
Zhang M, Poplawski M, Yen K, Cheng H, Bloss E, Zhu X, Patel H, Mobbs CV

How dietary restriction (DR) increases lifespan and decreases disease burden are questions of major interest in biomedical research. Here we report that hypothalamic expression of CREB-binding protein (CBP) and CBP-binding partner Special AT-rich sequence binding protein 1 (SATB-1) is highly correlated with lifespan across five strains of mice, and expression of these genes decreases with age and diabetes in mice. Furthermore, in Caenorhabditis elegans, cbp-1 is induced by bacterial dilution DR (bDR) and the daf-2 mutation, and cbp-1 RNAi specifically in adults completely blocks lifespan extension by three distinct protocols of DR, partially blocks lifespan extension by the daf-2 mutation but not of cold, and blocks delay of other age-related pathologies by bDR. Inhibiting the C. elegans ortholog of SATB-1 and CBP-binding partners daf-16 and hsf-1 also attenuates lifespan extension by bDR, but not other protocols of DR. In a transgenic Abeta42 model of Alzheimer's disease, cbp-1 RNAi prevents protective effects of bDR and accelerates Abeta42-related pathology. Furthermore, consistent with the function of CBP as a histone acetyltransferase, drugs that enhance histone acetylation increase lifespan and reduce Abeta42-related pathology, protective effects completely blocked by cbp-1 RNAi. Other factors implicated in lifespan extension are also CBP-binding partners, suggesting that CBP constitutes a common factor in the modulation of lifespan and disease burden by DR and the insulin/IGF1 signaling pathway.

PLoS One. 2009; 4(11): e7893
Uemura K, Lill CM, Li X, Peters JA, Ivanov A, Fan Z, Destrooper B, Bacskai BJ, Hyman BT, Berezovska O

BACKGROUND: Presenilin 1(PS1) is the catalytic subunit of gamma-secretase, the enzyme responsible for the Abeta C-terminal cleavage site, which results in the production of Abeta peptides of various lengths. Production of longer forms of the Abeta peptide occur in patients with autosomal dominant Alzheimer disease (AD) due to mutations in presenilin. Many modulators of gamma-secretase function have been described. We hypothesize that these modulators act by a common mechanism by allosterically modifying the structure of presenilin. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis we generated a genetically encoded GFP-PS1-RFP (G-PS1-R) FRET probe that allows monitoring of the conformation of the PS1 molecule in its native environment in live cells. We show that G-PS1-R can be incorporated into the gamma-secretase complex, reconstituting its activity in PS1/2 deficient cells. Using Förster resonance energy transfer (FRET)-based approaches we show that various pharmacological and genetic manipulations that target either gamma-secretase components (PS1, Pen2, Aph1) or gamma-secretase substrate (amyloid precursor protein, APP) and are known to change Abeta(42) production are associated with a consistent conformational change in PS1. CONCLUSIONS/SIGNIFICANCE: These results strongly support the hypothesis that allosteric changes in PS1 conformation underlie changes in the Abeta(42/40) ratio. Direct measurement of physiological and pathological changes in the conformation of PS1/gamma-secretase may provide insight into molecular mechanism of Abeta(42) generation, which could be exploited therapeutically.

Cell Cycle. 2009 Dec 17; 8(23):
Glinskii AB, Ma J, Ma S, Grant D, Lim CU, Sell S, Glinsky GV

Meta-analysis of genomic coordinates of SNP variations identified in genome-wide association studies (GWAS) of up to 712,253 samples (comprising 221,158 disease cases, 322,862 controls, and 168,233 case/control subjects of obesity GWAS) reveals that 39% of SNPs associated with 22 common human disorders are located within intergenic regions. Chromatin-state maps based on H3K4me3-H3K36me3 signatures show that many intergenic disease-linked SNPs are located within the boundaries of the K4-K36 domains, suggesting that SNP-harboring genomic regions are transcribed. Here we report identification of 13 trans-regulatory RNAs (transRNAs) 100 to 200 nucleotides in length containing intergenic SNP sequences associated with Crohn's disease, rheumatoid arthritis, type 1 diabetes, vitiligo, hypertension and multiple types of epithelial malignancies (prostate, breast, ovarian and colorectal cancers). We demonstrate that NALP1 loci intergenic SNP sequence, rs2670660, is expressed in human cells and may contribute to clinical manifestations of autoimmune and autoimflammatory phenotypes by generating distinct allelic variants of transRNAs. Stable expression of allele-specific sense and anti-sense variants of transRNAs markedly alters cellular behavior, affect cell cycle progression, and interfere with monocyte/macrophage transdifferentiation. On a molecular level, forced expression of allele-specific sense and anti-sense variants of transRNAs asserts allele-specific genome-wide effects on abundance of hundreds microRNAs and mRNAs. Using lentiviral gene transfer, microarray and Q-RT-PCR technologies, we identify rs2670660 allele-specific gene expression signatures (GES) which appear useful for detecting the activated states of innate immunity/inflammasome pathways in approximately 700 clinical samples from 185 control subjects and 350 patients diagnosed with 9 common human disorders, including Crohn's disease, ulcerative colitis, rheumatoid arthritis, Huntington disease, autism, Alzheimer disease, obesity, prostate and breast cancers. Microarray analysis of clinical samples demonstrates that rs2670660 allele-specific GES are engaged in patients' peripheral blood mononuclear cells (PBMC) which encounter pathological conditions in coherent tissues of a human body during immune surveillance and homeostasis monitoring. These data indicate that expression of transRNAs encoded by specific intergenic sequences can trigger activation of innate immunity/inflammasome pathways and contribute to clinical development of autoinflammatory and autoimmune syndromes. Documented in this work single-base substitution-driven molecular and biological antagonisms of intergenic SNP-containing transRNAs suggest a guiding mechanism of selection and retention of phenotype-compatible intergenic variations during evolution. According to this model, random genetic variations which generate transRNAs asserting antagonistic phenotype-altering effects compared to ancestral alleles will be selected and retained as SNP variants.